Surface modifications of biomaterials in different applied fields

Biomaterial implantation into the human body plays a key role in the medical field and biological applications. Increasing the life expectancy of biomaterial implants, reducing the rejection reaction inside the human body and reducing the risk of infection are the problems in this field that need to be solved urgently. The surface modification of biomaterials can change the original physical, chemical and biological properties and improve the function of materials. This review focuses on the application of surface modification techniques in various fields of biomaterials reported in the past few years. The surface modification techniques include film and coating synthesis, covalent grafting, self-assembled monolayers (SAMs), plasma surface modification and other strategies. First, a brief introduction to these surface modification techniques for biomaterials is given. Subsequently, the review focuses on how these techniques change the properties of biomaterials, and evaluates the effects of modification on the cytocompatibility, antibacterial, antifouling and surface hydrophobic properties of biomaterials. In addition, the implications for the design of biomaterials with different functions are discussed. Finally, based on this review, it is expected that the biomaterials have development prospects in the medical field.


Introduction
The development of modern medicine has made it possible to regenerate and rebuild damaged human tissues and organs. Biomaterials show strong vitality and broad development prospects in different medical elds. In this case, biological materials can be divided into metal materials, ceramic materials and polymer materials. 1 To date, a variety of materials based on polymers, ceramics and metals have been widely used in tissue engineering, including micro-implants for cardiovascular purposes and macroscopic devices in bone tissues, among many other applications. 2 Because of their excellent mechanical properties (high strength toughness and fatigue resistance) and chemical properties, metal-based biomaterials have been successfully applied as articial implants in the biomedical engineering eld. [3][4][5] The clinical application of ceramic and polymer materials as implants has also been widely studied. Even so, the utilized biological materials cannot avoid the occurrence of biocompatibility, protein adsorption, and bacterial adhesion. In this way, biocompatibility is the primary problem to be solved in surgical implantation. 6 Traditionally, biological materials implanted in the body will inevitably be rejected by the body, and the immune mechanism will show defense against them, leading to the failure of implantation of materials. 7,8 The growth of microorganisms in the implant leads to an increased rate of surgical infection. Most bacteria contaminating implants come from the skin surface and mucous membrane. These bacteria adhere to the surface of implant materials and proliferate to form biolms, leading to infection nally. 9 In this case, biolms can damage the tissue surrounding the implant, resulting in poor vascularization, loosening, detachment and even dislocation of the implant material. 10 Furthermore, the biolm formation process occurs via two stages: one is reversible interaction between bacteria and the surface of the biomaterial and the other one is an irreversible process, i.e. proteins on the surface of bacteria and the surface of the biomaterial could bind together to produce specic and non-specic interactions. 11 Biological contamination triggers foreign body reactions including nonspecic adsorption of proteins and adhesion of inammatory cells. Protein adsorption on the surface of biomaterials plays a key role in the subsequent processes of cell behaviour and extracellular matrix (ECM) formation. 12 The infection and inammation are the main causes of complications and failure of biomaterial implantation, both of which are caused by the interaction between cells and biomaterials. 9 Therefore, it is of vital importance to design medical biomaterials, which are both anti-fouling and anti-infective with highly biocompatible features. This not only signicantly improves the clinical outcomes, but also reduces the nancial burden of implant failure in patients.
The interaction of biomaterials with tissues is determined by their surface properties. Therefore, surface modication is considered as an important means to improve the biological properties. The surface modication of implanted biomaterials is an effective way to improve biocompatibility and reduce the incidence of associated infections. 13 It is common to modify the surface of biomaterials without changing the properties of the substrates on a micro or nano scale. 14,15 Surface modication provides controllable and programmable surface properties for biomaterials at the same time. It provides effective physical or chemical properties to make implanted biomaterials "more compatible" inside the human body. 16,17 Because of their advantages and disadvantages, these techniques can be used individually or in combination. 18 In this review article, the effects of surface modication on the properties of biomaterials were discussed from the perspective of chemical treatment and its combination with physics.
There are several surface modication strategies widely used in the modication of biomaterials, such as surface coatings and synthetic lms, covalent graing, self-assembled monolayers (SAMs), and plasma treatment (Fig. 1). Recently, several researchers have found that titanium (Ti), zirconia (ZrO 2 ), and polyetheretherketone (PEEK) have been used as orthopedic implants due to their excellent biocompatibility. The surface was modied with NaOH, which signicantly improved the water contact angle, protein adhesion and bioactivity of these materials. 19 Sharma et al. developed a stable, multifunctional, new-generation implantable urological biomaterial graed with polyethyleneimine and poly(2-ethyl-2-oxazoline), which showed excellent antifouling performance and biocompatibility. 20 As a coating agent, SAMs have antifouling properties on the surface of biomaterials and resist the adsorption of non-specic proteins. 21 Among the surface modications, hydrophobic surface is easy to cause protein adsorption, leading to biolm formation. Researchers introduce hydrophilic materials to the surface, such as synthetic coatings or plasma treatments that produce hydrophilic functional groups that resist non-specic protein adsorption and bacterial adhesion. 22 This review article mainly introduces several common surface modication strategies, focuses on the steps required by surface modication strategies and discusses the rationality of surface modication for biomaterials in medical applications. It includes biocompatibility, anti-infection and surface functionalization of biomaterials. In general, this kind of modication of biomaterials' surface (micro-nano scale) is benecial for us to improve the possibility of implant surgery and reduce medical costs.

Coating technology in surface modification processes
Surface modication techniques, in particular for biotechnological applications, were heavily pursued for creating extra physical or chemical properties as well as for designing and building potential interfaces. 23,24 A summary of the common surface modication strategies is given in Table 1. Since the creation of 45S5 bioglass by hench, it was utilized in clinical applications as a biocompatible coating material for hard tissue replacement and regeneration. 25 There have been several attempts to modify the makeup of bioactive glasses (BGs) in order to enhance their biological performance. Copper (Cu) exhibits antibacterial properties, and it has been reported that 45S5 bioactive glass can be fabricated by adding 5 wt% of CuO to the integrations. 26 The investigation of the inuence of Cucontaining bioactive glass on cellular behaviour has revealed that the presence of Cu induced an early differentiation of human mesenchymal stem cells (hMSCs) via the osteoblast phenotype, which promotes the expression of anti-inammatory interleukin and reduces proinammatory interleukin expressions. With the aim to produce coatings with antibacterial properties, the Cu-containing bioactive glass was used as the target material for the pulsed laser deposition (PLD) of bioactive thin lms. Chen et al. determined a surface modi-cation technique with excellent cohesive strength and durable coating stability, and in parallel, the modied layer exhibited a precise denition of chemical/biochemical conducts. They demonstrated a robust modication layer that was synthesized based on chemical vapor deposition (CVD) copolymerization. 27 The copolymer modication layer's characteristics such as its adhesive strength and thermal stability demonstrated remarkable endurance (Fig. 2a). In 2018, in order to further improve the osteogenic performance of tantalum coatings, Ding et al. proposed a new method for developing micro/nano tantalum (MNT) with layered structures by combining plasma spraying and anodic oxidation technologies. 28 During this process, it demonstrates that it can effectively enhance the proliferation and differentiation of human bone mesenchymal stem cells (hBMSCs) in vitro. Alena Richter et al. had proved that the Fe NP and brin can modify alginic acid salt and affect its wettability, surface roughness and elastic modulus. This, in turn, promotes the absorption of serum proteins, thereby promoting endothelial convergence by enhancing cell adhesion, proliferation, and vitality, thereby demonstrating a promising scaffold coating biomaterial. 29 These synergetic effects can pave the way toward a novel strategy for the modication of various hydrogel-based biomaterials and biomaterial coatings (Fig. 2b). Dulski et al. prepared a colloidal suspension, composed of b-TCP and the Ag/SiO 2 nanocomposites, which due to the electrophoretic deposition (EPD) led to the formation of structurally atypical calcium phosphosilicate coating. 30 The purpose was to improve the functionality of NiTi alloys and extend their medical stability. The focus of this idea was to use biocompatible multifunctional coatings without affecting the functionality of the substrate (Fig. 2c). Taking advantage of self-polymerization of DA, a multifunctional coating of polydopamine(doxorubicin)hydrophilic 2-methacryloyloxyethyl phosphorylcholine (PDA (DOX)-MPC) was constructed and modied on the intraocular lens (IOL) surface successfully. This coating was investigated by a series of experiments in vitro and in vivo. The measurement of water contact angle indicated that the IOL material has good hydrophilicity, which may lead to the biological adhesion between human lens epithelial cells and proteins. The drugrelease behavior indicates that the PDA (DOX) mpc-modied IOL material, as an original drug delivery system, has longterm sustained drug release characteristics (Fig. 2d). Biocompatible elements (niobium (Nb) and silicon (Si) were introduced into a TiO 2 matrix to change the surface chemical composition and tailor the thermophysical properties, which, in turn, leads to the generation of topographical features under specic thermal history of plasma spraying. The results indicate that the incorporation of Nb 2 O 5 can enhance the biological performance of TiO 2 coatings by changing the surface chemical composition and nanotopography, suggesting its potential use in the modi-cation of biomedical TiO 2 coatings in orthopedic applications. 32 Stepulane et al. presented a polydimethylsiloxane (PDMS) surface modication strategy of antibacterial coating. 33 Physical immobilization through the development of an interpenetrating polymer network allowed for the deposition of the microparticle coating made of cross-linked triblock copolymers (diacrylated Pluronic F127) on PDMS. A powerful antimicrobial peptide (AMP) was covalently immobilized on the surface of the produced coatings. With regard to Staphylococcus aureus and Staphylococcus epidermidis, it has a strong contact-killing antibacterial activity. Additionally, the coating's capacity to host polar, amphiphilic, and nonpolar medicines in a selective manner was evaluated, producing sustained release proles (Fig. 3a). Xiang et al. synthesized a series of poly(2-phenoxyethyl methacrylate-co-2-phenoxyethyl acrylate-co-2-ethylhexyl methacrylate) (PPPE) acrylic intraocular lens (IOL) materials for "glistening-free" optimization. 34 The 2-ethylhexyl methacrylate content in the chosen PPPE at 2% demonstrated good optical, foldable, and thermomechanical capabilities. Following gentamycin conjugation (PDA/GS), polydopamine was coated on the front side of PPPE. It reduced the thickness of the biolm by 87% and prevented bacterial adherence by 74%. Bacterial growth was controlled in the inammatory-mimicking conditions by acid-dependent GS release behavior. The PPPE surface remained hydrophobic as it approached the posterior capsule. The attachment of human lens epithelial cells, the adsorption of collagen IV and bronectin, and the subsequent development of a "sealed sandwich structure" were all made possible by this (Fig. 3b). 35 To efficiently prevent PCO, the hydrophobic surface of IOLs facilitates the inhibition of irregular migration and proliferation of human lens epithelial cells (HLECs). Therefore, an IOL material with a two-sided heterogeneous surface was needed. Photodynamic coating was introduced into the IOL surface modication. The photosensitizer chlorin e6-graed a-cyclodextrin (a-CD-Ce6) was synthesized and selfassembled onto poly(ethylene glycol) methacrylate (PPEGMA) brushes. It established the IOL surface via supramolecular interactions between a-CD and polymer chains. The results indicated that this functional coating modication was effective in eliminating cells from the IOL surface when treated with light, while sustaining cytocompatibility in the absence of light (Fig. 3c). The use of graing, assembly and other methods to improve hydrophilicity requires special equipment or complex preparation conditions, which has limitations in practical applications. However, the preparation process of surface coating modication technology is simple, and the coating thickness and composition ratio are controllable. The surface properties of biomaterials functionalized with surface-modied layers of surface coatings have been improved, such as good blood compatibility, enhanced cell behaviour, expansibility, good hydrophilicity and extended life of biomaterials. However, it is essential to improve the stability of the surface coating, which is prone to fall off into fragments and produce toxicity to surrounding cells and tissues.

Covalent grafting technology in surface modification processes
Chemical interactions are typical examples of establishing connections between different functional groups. It could be introduced as an important case of covalent graing technology. Generally speaking, chemical graing is more advantageous than physical methods because the covalent attachment of graed chains onto the substrate surface can avoid the desorption and ensure long-term stability. Further, due to the strong, selective, specic, and convenient reactivity of polymer brushes, polymer brushes that can be chemically graed to the surface have high adhesive strength. 36 Chemical surface modication methods usually based on the graing can be categorized into "graingto," "graing-from," and "graing-through" approaches 37 (Fig. 4a). It was commonly used for ensuring covalent graing of polymers. 38,39 In the graing-to approach, end-grouptransformed polymer chains reacted with the functional groups of substrates, which nally form graed polymer chains. In the graing-from approaches, polymer chains propagated from surface-attached initiators and polymer chains completely propagated from surface-attached double bonds. 40 The characteristic of the gra copolymer is controlled by the nature of graed chains, including number, length and molecular structure of graed chains. So far, extensive research has been conducted to explore the inuences of these parameters on the graing percentage and the characteristics of graed materials. 41 Covalent graing offers the strongest link work between biomaterials and its coating candidates, and it produces a more durable interface as much as possible. A summary of the common surface modication strategies is given in Table 2.
Naim et al. rst reported that the chemical medication of chitin by graing with polystyrene can use ammonium persulfate (APS) as an initiator. 42 Yu et al. prepared amphiphilic linoleic acid (LA) and poly(b-malic acid) (PMLA) double-graed chitosans with various graing degrees of linoleic acid (LA), which was modied with folate (FA) and poly(b-malic acid) PMLA. It was double-graed by the chitosan to probe the optimized hydrophobicity and hydrophilicity in a co-delivery system. This co-delivery system showed signicant enhancement in in vitro and in vivo antitumor efficiency while compared with single administration. 43 Chen et al. used functionalized chitosan/hydroxyapatite (CS/HA) biomimetic composite scaffolds for the controlled delivery of BMP2-derived peptides (P24) through chemically graing chitosan-4-thiobutylamidne (CS-TBA). Second, the resulting CS P24 was then combined with HA to prepare CS-P24/HA scaffolds. The effect of the CS-P24/HA scaffold on bone regeneration was evaluated, along with the underlying biological mechanisms. Finally, CS-P24/HA was superior to CS/HA in promotion of bone regeneration in vivo. This study highlights the enormous potential of using the CS-P24/HA scaffold for bone tissue engineering works. 44 Since an ultralow fouling surface is essential for good biocompatibility, Sun et al. attempted to further enhance the surface functionality using a novel solvent-free gra-from method. The graing was implemented by rst depositing a cross-linked polyvinylpyrrolidone (PVP) prime layer via initiated chemical vapor deposition (iCVD), followed by in situ polymerization on the top position without disrupting the vacuum. The propagating chains on the prime coating surface served as the initiating sites for the subsequent graing of PVP. The resulting coating thus consisted of a cross-linked prime layer and a top-graed PVP layer. 45 Liposomes are self-assembled vesicles of amphiphilic lipid molecules, and they are treated as cells, model of cells, or tools for drug delivery systems. Modications of polymer chains on the surfaces of liposomes are typically installed using a "graing to" approach, 47 as shown in Fig. 4b. Abdel-Rahman et al. prepared a 3D hybrid scaffold based on a collagen-grafted-chitosan-glucan ber (CO-g-CGF-HBS) by a freeze-drying technique. The swelling percentage, hydrolytic stability, and modulus of elasticity of HBS were enhanced aer the chemical modication of CO with CGF. The chemical modication of CO with different ratios of CGF signicantly improved the physicochemical and antibacterial properties of HBS. 46 The initial attachment of bacteria to the surface of implanted medical devices is the rst stage in biolm formation. Thus, the inhibition of bacterial colonization using antibacterial coatings, particularly during the most susceptible rst 6 h period aer implantation, is a fundamental strategy to prevent biolm formation. [48][49][50][51] To achieve ultralow fouling surfaces, hydrophilic polymer coatings such as polyethylene glycol (PEG) 52-55 and zwitterionic polymers 56,57 have been extensively explored. The graed chains generate a bound hydration layer that prevents the contact between foulants and the surface and induces a "cushion effect" repelling the approaching foulants. 55 Zhao et al. developed a PEG-and ACH 11 -functionalized surface. 58 Hydrophilic poly(ethylene glycol) (PEG) and antithrombotic peptide ACH 11 were co-immobilized onto Au to develop a multifunctional surface with remarkable hemocompatibility, protein adsorption, antiplatelet aggregation, anticoagulant properties, and good histocompatibility (Fig. 4c). Chou et al. reported that a facile, effective and economic graing-to method, which forms a stable chemisorption coating on versatile surfaces, was developed by the original design in the zwitterionic copolymer formulation of poly(glycidyl methacrylate-co-sulfobetaine methacrylate) (poly(GMA-co-SBMA)). 59 The epoxide functional groups of GMA segments could provide strong reactivity with nucleophiles via the ring-opening reaction. Thus, poly(GMA-co-SBMA) is capable of forming covalent bonding with versatile surfaces including polymer, ceramic, and metal substrates with hydroxyl groups aer surface pretreatment using UV and ozone, as shown in Fig. 4d. Masuda et al. hypothesized that ARGET ATRP could be used to modify a liposome surface by the graing-from method. 60 The molecular weight of the graed polymer chain was systematically controlled by changing the monomer concentrations in the "graing from" polymerization, as shown in Fig. 4e. Zhou et al. reported that ethyl ketones (AAEK) were covalently graed onto cellulose lms (CF) via a copper-catalyzed azide-alkyne 1,3dipolar cycloaddition click reaction. 61 The purpose of this study is to explore the effectiveness of surface-decorated aryl(b-amino) AAEK, a promised enzyme A (SrtA) inhibitor of Staphylococcus aureus, to improve the anti-adhesion ability of biomaterials. Du et al. synthesized and graed AACA onto the surface of PIB by plasma pre-treatment and UV-induced gra polymerization. 62 The hydrophilicity and hemocompatibility of PIB were largely improved by surface modication of aminocaproic acid (AACA), which were conrmed by water contact angle and platelet adhesion, respectively. Alvarez-Paino et al. reported a new approach for surface functionalization of poly(lactic acid) (PLA) microparticles that allows the decoration of the outer shell of the polyesters with additional functionalized poly(poly(ethylene glycol) methacrylate) and poly[N-(3-aminopropyl)methacrylamide] brushes, chosen for their potential abilities to mediate cell adhesion, 63 as shown in Fig. 4f.
In summary, the surface graing modication technology signicantly enhances the surface properties of biomaterials such as cell adhesion, hydrophilicity, biocompatibility, and stain resistance, while maintaining the same characteristics of the substrate material. Surface coating has the disadvantage of instability and easy shedding, while surface graing can enhance its stability in the physiological environment, and the graed chain can prevent dirt from contacting the surface of biomaterials. Obviously, the traditional organic solvent-based polymer graing method is lengthy and complicated, which is easy to contaminate the material surface. The solvent-free graing method can obtain better surface properties to a certain extent. Surface graing requires less energy and is more environmentally friendly than plasma surface modication techniques. The functionalization of spherical particles cannot be controlled uniformly by plasma treatment, and the morphology of the underlying material can also be altered. However, the limitation of surface graing may lead to inefficient antifouling properties, and the precise control of the synthetic process on the surface of biomaterials remains awed and needs to be improved.

Self-assembled monolayers as a surface modification strategy
Self-assembled monolayers (SAMs) are nano-thick ordered molecular coatings formed by molecular components adsorbed  Modied surfaces were found to be hydrophilic PDMS surface chemical properties were enhanced for the from solution or gas phase to solid surface and nally arranged in a regular manner. 64 The molecules from SAMs are well bound to the surface of the substrate material and have specic functional groups. A summary of the common surface modication strategies is given in Table 3. The SAM surface modication technology has been widely used in protein adhesion, cell adhesion, antibacterial and antifouling. The properties of biomaterials are mainly determined by the proteins adsorbed on their surfaces. 65,66 These proteins play a role in regulating cell adhesion, migration, proliferation and differentiation. 67 Therefore, it is essential to regulate the adhesion of proteins on the surface of biomaterials. Hasan et al. investigated the effect of SAM-functionalized biomaterials on protein adsorption. 68 The ability of Ti 6 Al 4 V to adsorb proteins and adhere to cells was tested by forming a hydrophilic, hydrophobic, and moderately hydrophobic monolayer on its surface. Similar as surface coating works, researchers controlled the surface properties of Ti 6 Al 4 V using a technique called silanization, which forms a covalent bond between the surface molecules linkages. It makes the biomaterials more stable and robust in performance (Fig. 5a). Lehnfeld et al. developed an in vitro model system based on silica surface in order to investigate the effect of adsorbed protein layers on the chemical modication of biomaterials. 69 It was modied by seven silanized SAMs. The results show that the chemical surface function of biomaterials greatly affects the total amounts of proteins adsorbed. Osteopontin (OPN) can mediate the cell behaviour of materials. 70 Chen et al. reported SAMs with different surface chemistries to investigate the behaviour of OPN on these SAMs. 71 The results indicated that the adsorption capacity of SAMs-NH 2 to OPN was stronger and the protein content was the highest. Meanwhile, in vitro cell experiments indicated that SAMs-COOH, SAMs-NH 2 and SAMs-PO 3 H 2 adsorbed with OPN can promote cell behaviour. It also proved that the SAM adsorbed with OPN has higher bioactivity, providing a new idea for the surface modication of biomaterials (Fig. 5b). Biomaterials oen come into contact with blood when implanted in the body and it is essential to avoid the adsorption of non-specic proteins on the surface. [72][73][74] Previous studies have shown that dendritic polyglycerin (dPG) protects biomaterial surfaces from non-specic protein adsorption and effectively reduces the adhesion of undiluted serum proteins. 75 In addition, a polyvalent form of dendritic polyglycerol sulfates (dPGS), which can effectively inhibit and bind to inammation in vivo, was introduced. 76 Stöbener et al. obtained a stable dPGS self-assembled monolayer on a gold substrate surface, which was acid-functionalized thioctic. 77 Compared with unsulfated dPGS, there are many negatively charged sulfate groups on the surface of dPGS, which enhance the adsorption of proteins under ionic interactions and lead to the partial rearrangement of the protein structures (Fig. 5c).
Cells attached to the surface of biomaterials can perceive and respond to chemical and physical surface features. 78,79 Therefore, the control of cell adhesion behaviour should be  81 Amino acidconjugated SAM-modied materials improved induced pluripotent stem cell (iPSCs) behaviour, and these functional groups with different surface functions had synergistic effects on iPSCs attachment, viability, and cardiomyocyte differentiation (Fig. 6a). Yeung et al. reported a reversible self-assembled monolayer (rSAMs) that achieves the dynamic control of surface composition and adjustable lateral uidity by adding inert ller amphiphiles to the tripeptide RGD-functionalized rSAMs, so as to achieve the purpose of regulating cell adhesion behaviour 84 (Fig. 6b). SAM-modied biomaterials have also been widely used in antibacterial and antifouling elds. In 2019, Acosta et al. used antimicrobial peptides (AMPs) and elastin-like recombinamers (ELRs) to design self-assembled monolayers. 85 The antibacterial properties of GL13K peptide and the low pollution activity of ELRs were combined and xed on the surface of gold substrates by covalent graing. The recombinant AMP/peptide SAM was evaluated to provide anti-biolm properties against Staphylococcus epidermidis and Staphylococcus aureus (Fig. 6c). Qiu et al. used a self-assembly method to covalently gra the chitosan layer onto the surface of PEEK by hydroxylation, introducing amino groups and glutaraldehyde crosslinking. 86 The method changes the surface morphology as PEEK increased the surface roughness and decreased the contact angle. The rough PEEK-CS surfaces are more likely to osteogenic than smooth PEEK-CS surfaces, which is attributed to the higher osteogenic activity of rough implant surfaces and in favour of cell adhesion, cell proliferation, and calcium nodule deposition. 87 The adhesion of bacteria on PEEK-CS to Porphyromonas gingivalis and Streptococcus mutans was decreased. Chitosan modication signicantly improved the osteogenic ability and antibacterial adhesion of polyether ether ketone in vitro (Fig. 6d).
Different from surface coating modication, self-assembled monolayers can form coatings on various metal surfaces with high exibility. At the same time, some SAMs also exhibit good thermal and hydrolytic stability. SAMs are controllable for cell adhesion and do not change the overall mechanical properties or surface roughness of the biomaterials, resulting in better biocompatibility of the materials. The different functional groups of the self-assembled monolayer make the interaction between cells and biomaterials different. The fabrication of selfassembled monolayers is simple and does not require expensive and sophisticated equipment. Although self-assembled monolayer-modied biomaterials have shown good antibacterial and osteogenic properties in vitro, in vivo antibacterial experiments are still insufficient. The long-term stability of functionalized biomaterials needs to be veried, especially for orthopedic and dental applications.

Plasma strategies in surface modification processes
Plasma is a substance that exists in the fourth state, which can be regarded as a collection of electrons, single-or multiple charged positive and negative ions accompanied by neutral atoms, excited particles, electromagnetic radiation, molecules, and molecular fragments which are in charge balance. 88,89 In most experimental situations, the plasma is generated by discharge. 88 It can generate the energy and produce plasma by applying electric and magnetic elds or even nuclear reactions. 90 This method has the advantage of only changing the surface properties of the material, such as surface chemistry, roughness, surface charge, and also enhancing the biocompatibility of the material, while the bulk properties of the material remain unchanged. 90,91 Gas plasmas can be generated under both atmospheric pressure and low-pressure conditions. 92 A large number of gases can be used in plasma, including argon, nitrogen, and argon-oxygen mixture, which are used to generate functional groups or free radicals on the surface of materials. These free radicals can improve the adhesion of the surface of biomaterials or gra other polymers on it to induce surface hydrophilicity. 93,94 Conversely, conventional gas plasma treatments and plasma immersion ion implantation can be conformal modied around the material, allowing treatment of 3D structures with high surface area and volume ratios with a wide range of internal porosity. 95 According to the interaction between the plasma and the surface of biomaterials, it can be divided into three categories: plasma polymerization, plasma treatment, and plasma gra etching. 94 Plasma surface modication techniques can be used directly or in combination with other surface modication techniques to achieve the purpose of enhancing the surface properties of biomaterials. 93 This section reviews the gas plasma strategy and plasma immersion ion implantation strategy in the literature in recent years, discussing and summarizing several studies on plasma treatment of different biomaterials to illustrate the importance of plasma technology in the surface modication of biomaterials. A summary of the common surface modication strategies is given in Table 4.
Xue et al. graed a layer of a-bromoisobutyryl bromide (initiator) on the surface of quartz substrates treated with oxygen plasma. 96 Subsequently, to protect the initiator from oxygen plasma corrosion in inclined reactive ion etching (RIE), a polymer lm was coated as a protective layer. 97,98 The geometric gradient was introduced into the prepared polystyrene (PS) microspheres array by inclining RIE. Since the polymer lm is etched away, the gaps between the initiators are lled with silica hydroxyl groups. Gradient polyhydroxyethyl methacrylate (PHEMA)/polyethylene glycol nanopatterned arrays were fabricated from gradient initiator/PEG nanopatterned arrays by surface-initiated atom-transfer radical polymerization (SI-ATAP) on quartz substrates. Finally, the protein was covalently immobilized on PHEMA nanodots, resulting in graded and ordered gradient protein/PEG nanopattern arrays (Fig. 7a). Gradient biomaterials based on plasma preparation can affect three basic behaviours of cells: adhesive density, polarization and migration. Phat et al. performed the surface modication of polylactic acid-glycolic acid (PLGA), collagen, and PLGA-collagen using a PDC-001 Expanded Plasma Cleaner. 99 The contact angles of water and diiodomethane on PLGA lms treated by argon plasma were signicantly decreased (p < 0.05), but had little effects on the thermal degradation of collagen and PLGA-collagen at high temperatures. The results of the bicinchoninic acid assay showed that the argon-plasma treated scaffolds released less collagen to PBS++ (p < 0.05). Mozaffari et al. used a PF-200 plasma DBD device to plasmonic electrospun nanober scaffolds with argon and an argon-oxygen mixture. 100 The surface of the untreated nanobers was smooth, while the surface roughness of the nanobers treated with argon and argon oxygen plasma was greatly increased, which was related to the bombardment of high-energy particles when the samples were treated with plasma. At the same time, the argon-oxygen plasma-treated nanobers exhibited a high degree of hydrophilicity, and the water droplets were completely absorbed into the scaffold, which was related to the introduction of polar groups. In contrast to air plasma modication, Onodera et al. formed uorine-containing diamond-like carbon (DLC) lms on a General-Purpose Polystyrene (GPPS) substrate using CH 4 and C 2 F 6 as gas sources. 101 Subsequently, the lm was subjected to atmospheric plasma treatment with oxygen to improve the biocompatibility of the lm. The lm has antibacterial properties, and uorine has an inhibitory effect on glucose metabolism for bacterial energy production. Physical changes have also occurred on the lm surface including increased hydrophilicity and decreased surface wettability to achieve the purpose of antibacterial activity. Kaleli-Can et al. used the plasma polymerization technique for surface modication with titanium using diethyl phosphite (DEP) as the gas source in an RF/lowpressure plasma device under 0.15 mbar. 102 The water contact angle of the DSP-coated Ti is signicantly smaller, and the surface energy is about two times higher than that of the unmodied Ti surface. The surface roughness was increased, and it had an inhibitory effect on C. albicans, which showed good antibacterial activity. Amphotropic plasmonic polymer prepared from DEP can effectively prevent biolm formation on the titanium surface. Ion implantation is the process by which positively charged ions in plasma are accelerated into the surface of a material. 103 Generally, the energy of the accelerated ion is much higher than the bond energy of the surface layer of the modied material, resulting in bond breaking. 104 Kondyurin et al. reported the silk broin biomaterials using plasma immersion ion implantation (c) Schematic of silk biofunctionalization with recombinantly expressed domain V (rDV) of human perlecan for blood contacting applications. (i) Schematic of the silk film biofunctionalization with rDV via passive adsorption (silk), carbodiimide chemistry (EDC/NHS silk) or nitrogen plasma immersion ion implantation (PIII silk). EDC/NHS-based protein immobilization occurs via formation of an amide bond between a carboxylic acid and a primary amine, typically occurring between aspartic/glutamic acid on silk and lysine on rDV. PIII-based immobilization relies on diffusion of mobile radicals from the PIII-treated silk surface to react with rDV. (ii) Schematic of the main structural and functional features of perlecan domain V expressed recombinantly in HEK-293 cells. rDV is a proteoglycan consisting of an 80 kDa protein core decorated with either a heparan sulfate (HS) or a chondroitin sulfate (CS) glycosaminoglycan (GAG) chain and has an a2b1 cell integrin binding site located at the C-terminus of the proteoglycan. (iii) Schematic of blood contacting assays used in this study with an increasing amount of blood components and complexity of interaction with the exposed surface. These are reprinted with permission from Xue et al. ( Fig. 7b). 105 PIII transforms the surface layer of the biomaterial into a compact carbon-rich structure with no signicant effect on its roughness. Due to the presence of free radicals during PIII treatment, the surface exposed to the atmosphere undergoes oxidation. PIII enhances silk interactions with proteins and cells. This provides a research direction for the application of silk broin biomaterials in tissue engineering and regenerative medicine in the future. It has been found that the biological activity can be improved by building functional groups. Guo et al. randomly divided the zirconia into four groups and used the corresponding parameters to modify the zirconia surface using plasma immersion ion implantation. 106 The surface roughness of the material was unchanged, the nitrogencontaining functional groups were introduced, and the stability of zirconia was not affected. In vitro data showed that PIII-treated zirconia promoted the adhesion, proliferation, and osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). Lau et al. used the PIII treatment technique to covalently immobilize recombinantly expressed domain V (rDV) on silk biomaterials, independent of immobilized proteins modied by specic amino acids in the silk protein chain. 107 The silk biomaterials biofunctionalized with rDV using PIII treatment show blood compatibility in terms of platelets (Fig. 7c). Different from plasma immersion ion implantation, researchers have also proposed ion implantation surface modication to improve properties such as biocompatibility, corrosion resistance and antibacterial properties.
In short, plasma-based surface modication techniques have great potential for biomaterial implants. Surface coating, self-assembling monolayers and ion implantation are limited to certain biological material chemistry or surface pretreatment. These chemical processes are time-consuming and complex, and require the addition of organic reagents, which may damage the implant. However, plasma surface modication technology has the advantages of short reaction time, environmental safety, and the ability to change the surface properties of the material without affecting the overall properties of the material. The interaction between plasma and some biomaterials can enhance their biocompatibility with biological cells, which can be used in tissue engineering. In addition, the lms prepared by plasma surface modication have the characteristics of thermal stability, chemical inertness, and enhanced toughness. Plasma surface modication can improve the surface wettability and cell attachment of biomaterials, and also improve their osteogenic and antibacterial properties. However, during the plasma process, the choice of the precursor can affect the properties of the biomaterial, leading to results that differ from the desirable properties. If the antibacterial layer on the surface of biomaterials lacks the killing and release mechanism, its antibacterial function will be weakened or even disappeared.

Other surface modification strategies
Appeared in healing of bone engineering, it lacks osteogenic activity of the implanted xation material and the infection of bacteria. 108,109 It is an important topic to pursue osteogenic activity and antibacterial properties. The previous reports have found that active ionic components play an important role in bone formation, development and repair, and that some metal ions can act as antibacterial agents. 110 Yang et al. prepared a protective coating containing Zn and Sr ions by a one-pot hydrothermal method. 111 Aer surface modication, a cluster of crystalline structures was formed on the surface of magnesium alloys. At the same time, the corrosion resistance of the magnesium alloy was signicantly improved, and the cells grew well on the surface. The combined use of Zn and Sr ions promoted the osteogenic differentiation of the cells with antibacterial effects. Kazimierczak et al. have synthesized magnesium (HA-Mg) and (HA-Zn) ion-substituted nano-hydroxyapatite (HA) synthesized to prepare a more biocompatible chitosanagarose-hydroxyapatite (HA) scaffold (chit/aga/HA). 112 These two above-mentioned metal ions have been found to have synergistic effects on the biological response in cell tests. The addition of Mg 2+ to this biomaterial structure can promote osteoblast spreading, promote cell proliferation on the scaffold surface, and promote osteocalcin production by mesenchymal stem cells. Moreover, the addition of Zn 2+ can promote the production of type I collagen by MSCs and extracellular matrix calcication. It has been found that the nanostructure on the surface of biomaterials has an important effect on cell activity and tissue formation. 113 Wen et al. added polydo and the physical properties were not changed. Shuai et al. reduced silver nanoparticles on carbon nanotubes (CNTs) in situ. 114 The CNT@Ag powder was then prepared by laser powder bed fusion (LPBF) to prepare the Zn-CNTs@Ag scaffold implant, which had an orthogonal porous structure that facilitates cell migration, tissue formation, and nutrient transportation. The scaffold exhibited favourable antibacterial activity and biocompatibility.

Conclusions and future prospects
As implanted in the human body, biomaterials have been widely used in the biological applications and clinical treatment. Especially in microbial infection, it is not easy to evitable in surgical implantation and resulted inammation, biolm harmful. Therefore, the surface modication could change the physical, chemical and biological properties of implant materials in order to improve the biocompatibility, antibacterial and antifouling properties. In this review, the main surface modi-cation strategies and methods are commonly illustrated. Among this, it is an effective way to enhance the antibacterial activity and reduce the adhesion of non-specic proteins and bacteria via surface modication of medical biomaterials. Towards hydrophilic contact angle, surface roughness, and surface functional groups, they ensured target material acceptable and biocompatible. Although the existing surface modication results are satisfactory, there are still many deciencies that need further investigations. First of all, the coating on the surface of the base material for a long time will cause different degrees of shedding, causing further infection. Second, surface modication increases the economic cost of biomaterials, and the modication process may pollute the environment. Lastly, higher complexity of the modication process also needs to be solved. In different strategies, there are differences in the interactions of human microenvironments. In fact, in vivo studies of surface-modied biomaterials are still lacking to further demonstrate their antibacterial properties and stability. The testing environment for the antimicrobial activity of a biological material should be relevant to the strains present in its application scenario. In order to guarantee the long-term stability of implants applied in orthopedics and dentistry under functional conditions, it is essential to test the mechanical properties of materials. In addition, the antibacterial properties, biocompatibility and other mechanisms of surface coatings or lms in physiological environments need to be investigated. Surface-modied biomaterials have a good prospect for clinical applications, but there are still difficulties in the preparation and processing of materials in large-scale production and development, and the realization of clinical translation and large-scale production needs to be optimized in future research. Therefore, future recommendations in this eld include reducing the additional cost of surface modication strategies, improving the stability of modied biomaterials, using facile approaches for further modifying biomaterials reasonably and achieving clinical translation.

Conflicts of interest
The authors declare no conict of interest.